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Biomedical subjects

G Brittenham

Publications and source records attributed to G Brittenham.

At least 19 recordsLinked to original sources
PubMed2001

Effect of primaquine standard dose (15 mg/day for 14 days) in the treatment of vivax malaria patients in Thailand.

Primaquine (8-aminoquinoline), the only effective drug to prevent relapses of the persistent liver forms of Plasmodium vivax and Plasmodium ovale, can induce hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The severity varies considerably among affected individuals. Three hundred and sixty-four Plasmodium vivax cases (342 G6PD-normal and 22 G6PD-deficient) were given a 3-day course of chloroquine (total dose 1,500 mg) followed by primaquine 15 mg a day for 14 days and completed a 28-day follow-up. All G6PD-deficient patients were male; there were no relapses or serious adverse events during the study. Although a significant decrease in hematocrit levels and an increase in the percent reduction of hematocrit levels were observed on day 7 (34.9+/-5.0 vs 26.7+/-5.4; (-1.2)+/-14.4 vs (-24.5) +/-13.9 respectively) and on day 14 (35.7+/-4.3 vs 30.9+/-3.1; 1.6+/-17.8 vs (-11.0) +/-19.3 respectively) blood transfusion was not required. Daily doses of 15 mg of primaquine for 14 days following a full course of chloroquine when prescribed to Thai G6PD deficient patients where Mahidol variant is predominant, are relatively safe.

Adult↗
PubMed2000

Thrombopoietin in Plasmodium falciparum malaria.

Thrombopoietin (TPO) is the key growth factor for platelet production and is elevated in states of platelet depletion. As thrombocytopenia is a common finding in malaria, we analysed TPO regulation before, during and after antimalarial treatment. Before treatment, TPO serum levels were significantly higher in patients with severe malaria (n = 35) than in patients with uncomplicated malaria (n = 44; P = 0.024), normalizing within 14-21 d of therapy. The rapid normalization of TPO levels and increase in low peripheral platelet counts after treatment indicate that the biosynthesis of TPO and its regulation in malaria patients are normal.

Acute Kidney Injury↗
PubMed2000

Contrasting functions of IgG and IgE antimalarial antibodies in uncomplicated and severe Plasmodium falciparum malaria.

Plasmodial infection results in a significant elevation of the blood concentrations of immunoglobulins including IgE. Two well-characterized groups of adult Thai patients with either uncomplicated or severe Plasmodium falciparum malaria were studied over a period of four weeks. The mean parasitemias were approximately three-fold higher in patients with severe malaria than in those with uncomplicated disease. The mean concentrations of both total IgG and IgG antiplasmodial antibodies tended to be highest in the group with uncomplicated disease while total IgE and IgE antibodies were higher in the group with severe disease. The IgE antibodies detected in approximately 65% of the patients were positively correlated to parasitemia. These results suggest that antiplasmodial IgG antibodies are involved in reducing the severity of P. falciparum malaria, while IgE antibodies may contribute to the pathogenesis of this infection.

Adolescent↗
PubMed1999

Iron primes hepatic macrophages for NF-kappaB activation in alcoholic liver injury.

NF-kappaB activation induced by lipopolysaccharide (LPS) in cultured hepatic macrophages (HM) may be abrogated by pretreatment of cells with a lipophilic iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1, deferiprone), suggesting a role for iron in this molecular event [M. Lin, M., R. A. Rippe, O. Niemelä, G. Brittenham, and H. Tsukamoto, Am. J. Physiol. 272 (Gastrointest. Liver Physiol. 35): G1355-G1364, 1997]. To ascertain the relevance in vivo of this hypothesis, HM from an experimental model of alcoholic liver injury were examined for the relationship between nuclear factor (NF)-kappaB activation and iron storage. HM showed a significant increase in nonheme iron concentration (+70%), accompanied by enhanced generation of electron paramagnetic resonance-detected radicals (+200%), NF-kappaB activation (+100%), and tumor necrosis factor-alpha (+150%) and macrophage inflammatory protein-1 (+280%) mRNA induction. Treatment of the cells ex vivo with L1 normalized all these parameters. HM content of ferritin protein, ferritin L chain mRNA, and hemeoxygenase-1 mRNA and splenic content of nonheme iron were increased, suggesting enhanced heme turnover as a cause of the increased iron storage and NF-kappaB activation. To test this possibility, increased iron content in HM was reproduced in vitro by phagocytosis of heat-treated red blood cells. Treatment caused a 40% increase in nonheme iron concentration and accentuated LPS-induced NF-kappaB activation twofold. Both effects could be abolished by pretreatment of cells with zinc protoporphyrin, a hemeoxygenase inhibitor. To extend this observation, animals were splenectomized before 9-wk alcohol feeding. Splenectomy resulted in further increments in HM nonheme iron storage (+60%) and NF-kappaB activation (+90%) and mononuclear cell infiltration (+450%), particularly around the iron-loaded HM in alcohol-fed animals. These results support the pivotal role of heme-derived iron in priming HM for NF-kappaB activation and expression of proinflammatory genes in alcoholic liver injury.

Animals↗
PubMed1998

Iron overload, public health, and genetics: evaluating the evidence for hemochromatosis screening.

Population screening for hemochromatosis done by using the transferrin saturation test has been advocated by experts to permit the initiation of therapeutic phlebotomy before the onset of clinical disease. The discovery of a gene associated with hemochromatosis has made DNA testing another option for screening and diagnosis. In this paper, U.S. Preventive Services Task Force criteria are used to evaluate the evidence for the usefulness of population screening done by using iron measures or genetic testing. Published clinical research offers little evidence to suggest that population screening for hemochromatosis done by using genetic testing improves clinical outcomes. Although one recently discovered mutation, C282Y, accounts for 60% to 92% of cases of the disease in series of patients with hemochromatosis, uncertainties remain about the clinical penetrance of various genotypes; the accuracy of genetic testing; and the ethical, legal, and social effects of genetic testing. Before population screening for hemochromatosis done by using transferrin saturation testing can be recommended, laboratory standardization needs to be addressed and questions about risk for clinical disease in asymptomatic persons with mutations or early biochemical expression of disease require resolution. Evidence from case series suggests that hemochromatosis may be associated with liver cancer, other liver disease, diabetes, bradyarrhythmias, and arthritis. In all studies but one, however, estimation of the magnitude and significance of this risk is limited by lack of adequate comparison groups. The need for population data to answer questions about penetrance among asymptomatic persons should not impede efforts to increase the detection and treatment of hemochromatosis in persons found to have elevated iron measures a family history of hemochromatosis, or consistent early signs and symptoms of the disease.

Hemochromatosis↗
PubMed1998

Hereditary hemochromatosis: gene discovery and its implications for population-based screening.

OBJECTIVE: To evaluate the role of genetic testing in screening for hereditary hemochromatosis to help guide clinicians, policymakers, and researchers. PARTICIPANTS: An expert panel was convened on March 3, 1997, by the Centers for Disease Control and Prevention (CDC) and the National Human Genome Research Institute (NHGRI), with expertise in epidemiology, genetics, hepatology, iron overload disorders, molecular biology, public health, and the ethical, legal, and social implications surrounding the discovery and use of genetic information. EVIDENCE: The group reviewed evidence regarding the clinical presentation, natural history, and genetics of hemochromatosis, including current data on the candidate gene for hemochromatosis (HFE) and on the ethical and health policy implications of genetic testing for this disorder. CONSENSUS PROCESS: Consensus was achieved by group discussion confirmed by a voice vote. A draft of the consensus statement was prepared by a writing committee and subsequently reviewed and revised by all members of the expert group over a 1-year period. CONCLUSIONS: Genetic testing is not recommended at this time in population-based screening for hereditary hemochromatosis, due to uncertainties about prevalence and penetrance of HFE mutations and the optimal care of asymptomatic people carrying HFE mutations. In addition, use of a genetic screening test raises concerns regarding possible stigmatization and discrimination. Tests for HFE mutations may play a role in confirming the diagnosis of hereditary hemochromatosis in persons with elevated serum iron measures, but even this use is limited by uncertainty about genotype-phenotype correlations. To address these questions, the expert group accorded high priority to population-based research to define the prevalence of HFE mutations, age and sex-related penetrance of different HFE genotypes, interactions between HFE genotypes and environmental modifiers, and psychosocial outcomes of genetic screening for hemochromatosis.

Female↗
PubMed1998

Pentoxifylline as an ancillary treatment for severe falciparum malaria in Thailand.

Pentoxifylline, an inhibitor of tumor necrosis factor, has been evaluated as an antimalarial agent in combination with artesunate in 45 patients with severe falciparum malaria. Patients were admitted to the intensive care unit at the Hospital for Tropical Diseases in Bangkok, Thailand, and randomly assigned to treatment for 72 hr with a combination of intravenously administered artesunate and 1) placebo, 2) low-dose pentoxifylline (0.83 mg/kg/hr), or 3) high-dose pentoxifylline (1.67 mg/kg/hr). All 45 patients had one or more manifestations of severe malaria such as cerebral malaria (n = 18), renal failure requiring hemodialysis (n = 9), azotemia (n = 8), jaundice (n = 25), or hyperparasitemia (n = 30). The overall severity was comparable in the three groups. Clinical outcome was assessed with respect to the parasite clearance time and the fever clearance time in all patients. In addition, a number of subsidiary outcome variables were examined in specific subgroups, including the recovery time from coma for patients with cerebral malaria, the duration of intubation in patients with respiratory distress, the number of hemodialysis treatments needed for patients with acute renal failure, and the number of units of blood administered to patients requiring transfusion. Concentrations of tumor necrosis factor were reduced in all three groups at 48 hr after treatment. No significant differences among the three treatment groups were found for any of the outcome variables examined. We conclude that the addition of pentoxifylline to artesunate therapy for severe malaria produced no evident clinical benefit.

Adolescent↗
PubMed1997

Role of iron in NF-kappa B activation and cytokine gene expression by rat hepatic macrophages.

A redox-sensitive nuclear factor, NF-kappa B, induces transcription of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in macrophages. The present study has investigated the role of iron in NF-kappa B activation and TNF-alpha and IL-6 expression by rat hepatic macrophages (HM). As an in vivo model, cholestatic liver injury was induced in rats by ligation of the common bile duct (BDL). During the first 2 wk after BDL, there was an increase in the hepatic level of thiobarbituric acid-reactive substances (TBARS) that was accompanied by the appearance of protein-malondialdehyde adducts in the periportal region. This increase was reduced after 3 wk. TNF-alpha and IL-6 mRNA levels in HM from the BDL rats were increased at 1 and 2 wk and attenuated at 3 wk. Gel mobility shift assay of HM nuclear extracts demonstrated the similar temporal pattern of enhanced NF-kappa B binding activity. Treatment of the BDL animals with 1,2-dimethyl-3-hydroxypyrid-4-one (L-1), a lipophilic iron chelator, suppressed the increases in hepatic TBARS by 64%, plasma alanine aminotransferase by 45%, and HM TNF-alpha and IL-6 mRNA by > 84%. Concomitantly, the HM NF-kappa B binding activity was reduced close to the level observed in sham-operated rats. Treatment of cultured HM with L-1 also blocked lipopolysaccharide-stimulated NF-kappa B activation and TNF-alpha and IL-6 expression at mRNA and protein levels. These results demonstrate that the iron chelator effectively blocks NF-kappa B activation and coordinate TNF-alpha and IL-6 gene upregulation by HM in cholestatic liver injury or under in vitro lipopolysaccharide stimulation. These findings support a pivotal role for iron in activation of NF-kappa B and cytokine gene expression by HM in vitro and in vivo.

Animals↗
PubMed1993

Contrasting interspecies efficacy and toxicology of 1,2-diethyl-3-hydroxypyridin-4-one, CP94, relates to differing metabolism of the iron chelating site.

In order to define a predictive animal model for the effects of hydroxypyridinone (HPO) iron chelators in humans, we have compared the 28 d oral efficacy and toxicology of the HPO, 1,2-diethyl-3-hydroxypyridin-4-one (CP94) in rats and guinea-pigs and related the results to the contrasting metabolism of this compound in the two species. CP94 was highly effective at mobilizing liver iron in rats but showed toxicity at higher doses, whereas in the guinea-pig the compound lacked toxicity but was ineffective at mobilizing liver iron. These differences can be explained by the contrasting metabolism of the drug between the two species. In rats, at the top dose of 300 mg/kg intragastrically, all animals died before the end of the study, with no deaths or weight loss at lower doses. At 100 mg/kg, rat liver non-haem iron concentrations were reduced by 53% and 44% in females and males respectively (P < 0.001). At this dose, adrenal medullary cell vacuolation, increased mammary secretory activity, vacuolation of corpora luteal cells and single cell hepatocyte necrosis were seen. There were no reductions in the white cell count. At 50 mg/kg rat liver non-haem iron concentrations were decreased by 50% and 34% in females and males respectively (P < 0.02). In female rats this was associated with increased mammary secretory activity. In iron-overloaded rats given 100 mg/kg by gavage for 28 d, liver non-haem iron concentration was reduced by 39% (P < 0.01) and serum ferritin by 71% (P < 0.001). Ovarian and mammary changes were not influenced by iron loading. In guinea-pigs, CP94 was evaluated at 50 mg/kg, 100 mg/kg or 200 mg/kg by oral insufflation for 28 d. No reduction in liver iron was seen and no systematic dose related histological, biochemical or haematological effects were observed. Whereas in guinea-pigs 99% of urinary recovery following an oral dose of CP94 (100 mg/kg) was as the inactive glucuronide metabolite, in the rat only 23% of the dose was excreted in the urine as the glucuronide with remainder as the free drug or an iron binding metabolite. The lack of both efficacy and toxicity in the guinea-pig may therefore be explained by the rapid inactivation of CP94 by glucuronidation. This metabolism of CP94 in the guinea-pig is closer to humans than the rat, suggesting that both the efficacy and toxicity of this compound in humans may also be limited by glucuronidation.

Animals↗
PubMed1992

Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria.

BACKGROUND: Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15 to 50 percent despite antimalarial therapy. METHODS: To determine whether combining iron chelation with quinine therapy speeds the recovery of consciousness, we conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be less than six years old, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they could not be aroused. Deferoxamine (100 mg per kilogram of body weight per day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pyrimethamine. The time to the recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis. RESULTS: The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 times that among the 41 given placebo (95 percent confidence interval, 0.7 to 2.3); the median time to recovery was 20.2 hours in the deferoxamine group and 43.1 hours in the placebo group (P = 0.38). Among 50 patients with deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95 percent confidence interval, 1.1 to 4.7), decreasing the median recovery time from 68.2 to 24.1 hours (P = 0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95 percent confidence interval, 1.2 to 3.6). Among all 83 patients, mortality was 17 percent in the deferoxamine group and 22 percent in the placebo group (P = 0.52). CONCLUSIONS: Iron chelation therapy may hasten the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.

Child, Preschool↗
PubMed1990

Second fingerstick: a simple method to increase the blood supply.

Before blood donors are deferred because of a low hemoglobin determination by the copper sulfate procedure, they are routinely retested with a microhematocrit. The copper sulfate test and the microhematocrit usually are performed on blood samples taken from the same finger (or earlobe) puncture. We studied 201 male and female volunteer blood donors who failed the copper sulfate test to determine if more donors would be accepted for donation if blood from a second fingerpuncture, instead of the original fingerstick, was used for the microhematocrit determination. Venous blood samples were obtained to evaluate complete blood count and measures of iron status. The results indicated that the deferral rate was reduced by 46% using a fresh fingerpuncture for the microhematocrit determination. The iron status of the additional donors accepted on the basis of the second puncture was not significantly different from that of the donors accepted by the original fingerstick. We conclude that using a second fresh fingerpuncture for the microhematocrit determination after failing the copper sulfate test decreases the number of hematocrit deferrals and does not compromise the iron status of the additional donors.

Blood Donors↗
PubMed1988

The effect of erythroid hyperplasia on iron balance.

Measurements of erythropoiesis and iron balance were made in eight normal and 32 anemic subjects. The latter consisted of 12 individuals with ineffective erythropoiesis (beta-thalassemia/hemoglobin E), 13 subjects with ineffective erythropoiesis and hemolytic anemia (hemoglobin H), and seven subjects with hemolytic anemia (hereditary spherocytosis). A consistent relationship within each group existed between the degree of erythropoiesis and radioiron absorption. Although the effect of erythropoiesis on iron absorption was of similar magnitude in the two thalassemia groups, the effect in hereditary spherocytosis was much less. There was agreement between absorption and ferritin or magnetic susceptibility (SQUID) measurements of iron stores in thalassemia, but in hereditary spherocytosis a discrepancy existed between absorption and ferritin. It is concluded that, although increased erythropoiesis is associated with increased iron absorption, some additional factor associated with red cell breakdown is more directly responsible for the positive iron balance in thalassemia.

Adolescent↗
PubMed1980

Alpha globin gene number: population and restriction endonuclease studies.

Restriction endonuclease analysis was used to test a proposed genetic model using alpha-globin gene number to account for the observed distributions of the proportions of hemoglobin (Hb) S in sickle cell trait. In a subsample of specimens collected during a population survey in India, these studies confirmed that the postulated genotype was present in 22 of the 23 individuals examined. In the study population, the number of alpha-globin genes explains about 90% of the variance in the proportion of HbS in sickle cell trait (r2 = 0.895, p less than 10(-10)).

Anemia, Sickle Cell↗
PubMed1979

Spectrophotometric plasma iron determination from fingerpuncture specimens.

A simple, sensitive, precise and reproducible micromethod for the determination of plasma iron in a 50-microliter sample has been devised by modification of the ICSH reference procedure, which requires a 2-ml sample. The micromethod uses microcuvettes and substitutes ferrozine for the bathophenanthroline chromogen of the ICSH. Comparison of plasma iron values on 47 paired specimens obtained by fingerpuncture and venipuncture determined by the micro- and ICSH-methods respectively gave identical means of 15.8 mumol/l (88 microgram/dl); the correlation of the two methods was r = 0.92 (p less than 0.0001). The micromethod has been successfully used to measure plasma iron levels in fingerpuncture specimens collected in a field study of 429 children.

Adult↗
PubMed1979

Sickle cell anemia and trait in southern India: further studies.

Population surveys and family studies among 568 members of nine ethnic groups in southern India identified 15 homozygotes for sickle hemoglobin (HbS)who had mild clinical and hematological manifestations with high levels of fetal hemoglobin (mean=20%, range 8-36%) in a heterogeneous red cell distribution. In one family, the heterozygous mother had a hemoglobin pattern consistent with a form of the heterocellular hereditary persistence of fetal hemoglobin. Sickle cell trait was found in 153(27%) of those studied. Chromatographic quantitation of the hemoglobin fractions in these heterozygotes showed a trimodal distribution of the proportion of HB Sexplicable by a genetic model postulating the presence of genotypes with two (-alpha/-alpha), three (-alpha/alpha alpha) and four (alpha alpha/alpha alpha) active alpha-globin genes. Globin synthesis studies in four heterozygotes believed to have two active alpha-globin genes demonstrated an alpha/non-alpha total activity ratio (0.57) consistent with this model.

Anemia, Sickle Cell↗
PubMed1979

Infant care: cache or carry.

To test the hypothesis that a characteristic infant-care pattern existed during most of human history, contemporary hunter-gatherers in a representative sample of world cultures were examined. Numerically coded measures of infant care revealed a uniform pattern. Mothers are the principal caregivers, providing extensive body contact day and night and prolonged breast-feeding. When not carried, the baby of hunter-gatherers has complete freedom of movement. Care is consistently affectionate, with immediate nurturant response to crying. Nonetheless, in most groups, children achieve early independence and by 2 to 4 years spend more than half the time away from the mother. In the United States this pattern of carrying that endured for one to three million years has been replaced by one resembling nesting or caching. Infants spend little time in body contact with caregivers and their movements are restricted by playpens, high chairs, or cribs. Of the minority who are breast-fed, half are weaned within a few weeks. Separate sleeping arrangements and delayed response to crying are regularly recommended. These remarkable transformations may profoundly alter infant development and maternal involvement.

Africa↗
PubMed1978

Hemoglobin Hofu or alpha 2 beta 2 [126 (H4) Va1 leads to Glu] found in combination with hemoglobin S.

Hb Hofu, alpha 2 beta 2 [126 (H4) Va1 leads to Glu], was found in 10 members of 2 apparently unrelated Valmiki families in central India. None showed evidence of hemolysis and hemoglobin levels were normal in most. In two individuals, Hb Hofu occurred in combination with Hg S, but neither had clinical manifestations of sickle cell disease. In samples containing Hb Hofu, the isopropanol precipitation test was positive. Quantitation of the hemoglobin fractions by DEAE-cellulose chromatography showed that Hb Hofu constituted a mean of 23--25% of the total whether in combination with Hb A or Hb S.

Female↗